Obesity is a common, serious, and costly disease that affects 33% of US citizens and 37% of VA patients. Although therapeutic treatments remain elusive, recent scientific evidence has pointed to enteroendocrine cells - sensory cells of the gut - as potential solutions. These cells are known to secrete several neuropeptides that are potent inducers of satiety, like cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), and peptide YY (PYY), and their sensory mechanisms have been the subject of intensive investigation. However, how these cells transduce their sensory signals onto neurons and other cells is largely unknown. We recently developed novel transgenic mouse models to study these cells by expressing enhanced green fluorescent protein (eGFP) in CCK- or PYY-containing cells. The eGFP models allowed us to discover that enteroendocrine cells have prominent basal cytoplasmic processes with similar features to neuronal axons. These basal cytoplasmic processes, we found, directly connect to neuronal afferents and efferents innervating the gut mucosa. The present proposal is designed to elucidate the function of this connection. Our central hypothesis is that basal cytoplasmic processes are essential in the exchange of molecular information between enteroendocrine cells and sensory neurons. This hypothesis is built on preliminary data produced in the PI's laboratory and will be tested by pursuing the following specific aims: Aim 1 is to characterize the connection between enteroendocrine cells and sensory neurons Aim 2 is to determine how the formation of enteroendocrine cell cytoplasmic processes is regulated Aim 3 is to define the effects of diet-induced obesity on the neuro-enteroendocrine connection We anticipate that the characterization of gut neuroendocrine signaling will facilitate the development of strategies to modulate the transmission of sensory information from enteroendocrine cells to neurons and vice versa. Because these sensory signals ultimately participate in the regulation of food intake and appetite, elucidating the mechanisms that regulate this connection can provide novel therapeutic approaches to treat obesity.